Effect ofd-fenfluramine on the indole contents of the rat brain after treatment with different inducers of cytochrome P450 isoenzymes

Abstract

The effects of pretreatment with inducers of hepatic cytochrome P450 isoenzymes (phenobarbital, dexamethasone and beta-naphthoflavone) on the metabolism of d-fenfluramine (d-F) and its acute and long-lasting indole-depleting effects were studied in rats, in an effort to obtain further information on the importance of hepatic drug metabolism in relation to its neurochemical actions. Twenty-four hours after the last dose of each inducer, rats were injected with d-F hydrochloride (5 mg/kg, IP) and killed at various times thereafter for parallel determination of indoles and drug concentrations in plasma and brain. Additional rats were treated as above and killed 1 week after d-F hydrochloride (5 and 10 mg/kg) to study the recovery of indole in the cortex, a particularly sensitive brain area. Phenobarbital and beta-naphthoflavone and, to a lesser degree, dexamethasone, stimulated the metabolism of d-F, as evidenced by a decrease in plasma and brain areas under the curve (AUC) compared to vehicle-treated rats. This indicated that multiple isoenzymes are capable of mediating the drug's metabolism, primarily by N-dealkylation to d-norfenfluramine (d-NF). None of the inducers raised plasma and brain AUC of the nor-derivative, and in fact phenobarbital and particularly beta-naphthoflavone reduced it. These different effects were even apparent in rats given d-NF (2.5 mg/kg), indicating that both phenobarbital and beta-naphthoflavone also stimulate the sequential metabolism of the nor-metabolite (by N-deamintaion) which, however, is apparently enhanced most actively by beta-naphthoflavone-inducible forms of P-450.(ABSTRACT TRUNCATED AT 250 WORDS)